Beryllium: Exposure, Immune and Genetic Mechanisms

铍：暴露、免疫和遗传机制

基本信息

批准号：
7643566
负责人：
LISA A MAIER
金额：
$ 10.93万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-12 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643566
关键词：
Address Adjuvant Adrenal Cortex Hormones Adverse effects Affect Affinity Alloys Aluminum Antigen Presentation Antigen-Presenting Cells Antigens Antioxidants Applications Grants Area Australia Avidity Basic Science Belgium Berylliosis Beryllium Bicycling Biological Assay Biological Markers Biological Models Biometry Biopsy Blocking Antibodies Blood Blood specimen Breathing Bronchoalveolar Lavage Bronchoscopy CD4 Positive T Lymphocytes Canada Caring Cell Communication Cell Line Cell physiology Cells Chronic Chronic berylliosis Class Clinic Clinical Clinical Data Clinical Immunology Clinical Markers Clinical Research Clinical assessments Cohort Studies Collaborations Colorado Computers Condition Copper Coughing Cytokine Gene Cytokine Network Pathway DNA Data Data Base Management Databases Dental Alloys Depth Detection Development Diagnosis Discipline Discipline of Nursing Disease Disease Management Disease Outcome Disease Progression Doctor of Philosophy Dose Early Diagnosis Economics Effectiveness Electronics Elements Environment Environmental Exposure Epidemiology Evaluation Exercise Exposure to Extrinsic allergic alveolitis Faculty Failure Fatigue Fibrosis Follow-Up Studies France Funding Future Gases Gene Expression Gene Expression Regulation Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Genotype Germany Goals Golf Grant Granuloma Granulomatous HLA-DP Antigens HLA-DPB1 gene Head Health Health Sciences Heating Hereditary Disease Histocompatibility Human Immune Immune response Immune system Immunogenetics Immunologic Tests Immunologics Immunology Immunosuppressive Agents In Vitro Indium Individual Industry Inflammation Inflammatory Inflammatory Response Informatics Informed Consent Injury Integration Host Factors Interferon Type II International Interstitial Lung Diseases Invasive Investigation Israel Japan Kazakhstan Laboratories Lead Learning Limb structure Link London Longitudinal Studies Lung Lung diseases Maintenance Major Histocompatibility Complex Major Histocompatibility Complex, Class II, DP Beta 1 Measures Mediating Mediation Medical Research Medical Surveillance Medicine Metalloporphyrins Metals Methods Methotrexate Modeling Molecular Molecular Epidemiology Molecular Genetics Molecular Immunology NIH Program Announcements Names National Institute for Occupational Safety and Health Natural History Natural Immunity Nature Nuclear Weapon Numbers Occupational Occupational Medicine Occupations Organ Outcome Measure Oxidants Oxidative Stress Participant Particulate Pathogenesis Pathology Pathway interactions Patients Pattern Peptide T Peptides Performance Personal Satisfaction Plants Population Population Genetics Predisposition Principal Investigator Process Production Program Research Project Grants Property Protein Overexpression Publishing Qualifying Quebec Range Rate Recording of previous events Recycling Regulation Regulator Genes Relative (related person)Reporting Research Research Design Research Methodology Research Personnel Research Project Grants Resources Respiratory physiology Rest Risk Risk Factors Role Sampling Sarcoidosis Schedule Science Screening procedure Sensitivity and Specificity Severities Severity of illness Shortness of Breath Site Specificity Specimen Stimulus Stress Structure Study Subject Superoxide Dismutase Sweden Symptoms System T-Cell Proliferation T-Cell Receptor T-Lymphocyte Technology Testing Time Tissues Translational Research Translations Tumor Necrosis Factor-alpha United Kingdom Universities Up-Regulation Validation Weight Work Workplace acquired immunity base bench to bedside case control clinical phenotype clinically relevant clinically significant cohort college cost cytokine data integration data management day design desire disorder control disorder prevention disorder risk experience exposed human population follow-up follower of religion Jewish forging gene environment interaction genetic epidemiology human disease in vitro Model in vivo interdisciplinary approach interest lymphocyte proliferation melting member mimetics novel novel therapeutics outcome forecast pre-clinical prognostic programs promoter research clinical testing research study response sample collection skills success tool

项目摘要

Beryllium sensitization and chronic beryllium disease (CBD) continue to affect individuals who have occupational or environmental exposure, especially those with genetic susceptibility. The long-term objectives of this Program Project Grant are to evaluate the basic immune and inflammatory mechanisms underlying beryllium sensitization and chronic beryllium disease, and to establish the relationship between beryllium exposure and immunogenetics. The proposal consists of four projects and three core units. Project 1 will determine the mechanisms by which beryllium induces aberrant, high production of the pro- inflammatory cytokine tumor necrosis factor-alpha in CBD, focusing on the priming effects of interferon-gamma and direct effects of beryllium sensitization, in the progression from sensitization to CBD, and in the development of severe forms of this granulomatous disorder. Project 3 will determine the role of beryllium-reactive CD4+ T cells and the affinity of the T cell antigen receptor for the beryllium/peptide/major histocompatibility (MHC) complex. In doing so, this project will determine qualitative and quantitative differences in T cell recognition of beryllium, in the ability of beryllium-specific CD4+ T cells to secrete pro-inflammatory cytokines, utilizing this information to develop biomarkers of disease progression. Project 4 will determine the role of oxidative stress in enhancing the antigen presenting cell's ability to present beryllium antigen to T cells. It will test the hypothesis that beryllium induces oxidative stress which promotes an excessive cytokine response and T cell proliferation in CBD. The overall rationale for the Program Project is to use an interdisciplinary approach to define the genetic underpinnings of the cellular response to beryllium, to relative mechanisms to human exposure risk factors, and develop new biological markers of CBD risk, disease progression, and prognosis.

铍敏化和慢性铍疾病（CBD）继续影响具有职业或环境暴露的人，尤其是那些具有遗传敏感性的人。该计划项目赠款的长期目标是评估铍致敏和慢性铍疾病的基本免疫和炎症机制，并确定铍暴露与免疫遗传学之间的关系。该提案由四个项目和三个核心单位组成。项目1将确定铍诱导异常的机制，高炎性细胞因子肿瘤坏死因子因子-Alpha在CBD中，重点关注干扰素伽马的启动效应以及铍的直接效应，在从敏感性到CBD的进展中，以及这种严重的静脉曲张的发展中的促进作用。项目3将确定铍反应性CD4+ T细胞的作用以及T细胞抗原受体对铍/肽/主要组织相容性（MHC）复合物的亲和力。在此过程中，该项目将确定铍特异性CD4+ T细胞分泌促炎细胞因子的T细胞识别的定性和定量差异，利用这些信息来发展疾病进展的生物标志物。项目4将确定氧化应激在增强抗原表现出细胞向T细胞中抗原表现出铍的能力方面的作用。它将检验以下假设：铍诱导氧化应激，从而促进CBD中过度的细胞因子反应和T细胞增殖。该计划项目的总体原理是使用跨学科的方法来定义细胞对铍的遗传基础，对人类暴露风险因素的相对机制，并发展CBD风险，疾病进展和预后的新生物学标志物。